{"doi":"10.13023/etd.2020.329","title":"Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer","abstract":"Triple negative breast cancer (TNBC) comprises 15-20% of breast cancers, affects a younger patient population than other subtypes, and is very aggressive. TNBC is comprised of a diverse group of tumors that have proven refractory to targeted therapy and can be difficult to treat. Patients generally receive neoadjuvant chemotherapy (NAC), surgery, and radiotherapy. The standard of care for NAC includes a taxane, an anthracycline, and/or cyclophosphamide, and administration of NAC has resulted in pathological complete response (pCR) in 30-40% of patients. However, a majority of TNBC patients will not reach pCR and instead have residual disease (RD), which is associated with worse outcomes. Patients with RD are more likely to experience locoregional or distant recurrence, and they have lower rates of overall survival, breast cancer-specific survival, disease-free survival, and distant relapse-free survival. Five-year survival rates for TNBC are 91% for localized disease, 65% with regional recurrence, and only 11% with distant recurrence. The reductions in survival with metastasis indicate that patients who have RD after receiving NAC desperately need novel interventions. AMP-activated protein kinase (AMPK) and protein kinase B (Akt) are important cellular energy regulators that have been implicated in cancer therapy and progression. However, further work is needed to fully establish their roles as therapeutic modalities in TNBC. This study analyzed whether targeting the AMPK and Akt signaling pathways can enhance TNBC therapy or reduce TNBC metastasis. Chemical activation of AMPK suppresses growth of cancer cells, but many common AMPK activators—such as AICAR or 2-deoxyglucose—have low sensitivity and require dosing in the millimolar range. This has led to their unsuccessful translation to the clinic. FND-4b is a novel compound that activates AMPK at micromolar concentrations in colorectal cancer cells, but its effects in TNBC are unknown. Treatment of TNBC cells with FND-4b induced AMPK activation and signaling through its downstream pathways. Phosphorylation of acetyl CoA carboxylase (ACC)—a direct target of AMPK—was increased, indicating a decrease in fatty acid synthesis. Furthermore, activation of ribosomal protein S6 was reduced, which suggests reduced flux through the mTOR pathway. FND-4b also suppressed proliferation of TNBC in a dose-dependent manner in the low micromolar range, which is substantially lower than well-known AMPK activators. Finally, FND-4b increased apoptosis induction in TNBC cells at micromolar doses. Taken together, these findings indicate that FND-4b reduces proliferation and induces apoptosis through AMPK activation in TNBC cells at lower doses than many other AMPK activators. AMPK inhibition has increased sensitivity of cancer cells to radiotherapy due to suppression of autophagy. Chemical inhibition of the PI3K signaling cascade has also potentiated radiation-induced cell death in TNBC cells. However, the ability of individual AMPK or Akt isoforms to sensitize TNBC cells to radiotherapy has not been studied. Moreover, while a double-negative feedback loop exists between AMPK and Akt—a downstream effector of PI3K—the impact of combined inhibition of AMPK and Akt isoforms on TNBC survival after radiation is unknown. Immunohistochemical (IHC) staining indicated that AMPKα1 is expressed in only the cytoplasm of TNBC, while AMPKα2 is found in both the cytoplasm and the nucleus. AMPKα1 or AMPKα2 knockdown decreased proliferation and induced G1 cell cycle arrest in TNBC cells but did not induce apoptosis alone or in combination with radiotherapy. The role of PI3K p85α, p85β, p110α, p110β, Akt1, and Akt2 proteins on TNBC cell cycle progression and apoptosis induction was then analyzed. Akt1 and p110αsuppressed cyclin D1 expression and induced apoptosis. Silencing Akt1 potentiated radiation-induced apoptosis and further suppressed survival of TNBC cells after radiation exposure. Treatment of TNBC cells with","journal":"UKnowledge (University of Kentucky)","year":2020,"id":131029,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":584967,"name":"Jeremy Andrew Johnson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":113,"raw_metadata":null,"created_at":"2026-07-18T23:16:00.235845Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}